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1 January 1996
Dyslipoproteinemia of
FOCAL POINT
Chronic Renal Failure:
★ Control of dyslipoproteinemia
may become important in
Its Relevance to
the treatment of renal failure
in dogs. Canine Progressive
KEY FACTS Kidney Disease
■ The dyslipoproteinemia that
results from renal disease may
contribute to the progression of University of Illinois
renal failure. Lisa Kurosky Down, DVM
Donald R. Krawiec, DVM, PhD
■ Reduction of hyperlipidemia
through diet or medication has
reduced renal damage in
experiments with various species.
Lipoprotein Metabolism
Chylomicrons absorbed from the gastrointestinal depends on the concentration, distribution, and func-
tract and VLDL particles formed by the intestine and tion of these important proteins.
liver are composed mainly of triglycerides, which are re-
leased to tissue by the action of lipoprotein lipase en- SPECIES COMPARISON
zymes. Low-density lipoprotein particles formed by the Lipoproteins are fairly similar across species; however,
liver are the major carriers of cholesterol in humans and some differences exist.10 In dogs, for example, HDL
are taken up as needed by tissue through interaction particles carry most of the serum cholesterol (Tables II
with a specific LDL receptor.11–13 High-density lipopro- and III). Also, a cholesterol-laden HDL subclass (HDLc
teins are responsible for transporting cholesterol back or HDL1) is a routine finding in canine lipoprotein
to the liver. Through the action of the enzyme profiles but is not typically seen in healthy individuals
lecithin:cholesterol acyltransferase and cholesterol ester of other species.18–20 The density ranges are slightly dif-
transfer protein, HDL particles can transfer cholesterol ferent for canine lipoproteins than for those of humans
between lipoprotein molecules and return cholesterol (Table I). Figure 1 compares the agarose gel elec-
to the liver for excretion.11–13 trophoresis of human lipoproteins with that of canine
lipoproteins.21 However, no great differences in the
Apoproteins metabolic functions of the lipoprotein classes between
In healthy individuals, the particles within each class these species have been noted.
of lipoprotein have characteristic profiles of apolipopro-
teins or apoproteins on their surfaces. For example, apo DYSLIPOPROTEINEMIA
B-48 is found exclusively on chylomicron particles The dyslipoproteinemia observed in humans with
whereas apo B-100 is primarily associated with LDL.12 nonnephrotic chronic renal disease is characterized by
Apo A-I and apo A-II predominate in HDL parti- changes in the proportion of triglycerides and choles-
cles.12,14 Apoproteins determine the metabolic functions terol within lipoprotein classes. Affected humans exhib-
of the lipoprotein particles by binding with various it elevations in the triglyceride fraction of VLDL, LDL,
lipoprotein receptors as well as through other interac- and HDL molecules.1,5 Blood levels of triglyceride may
tions. For example, apo B-100 and apo E are both li- or may not be elevated coincidentally, depending on
gands for LDL receptors12,13,15,16 whereas apo C inhibits the severity of the disease.7 Total cholesterol is usually
the uptake of particles that contain apo E.17 Apo A-I, moderately increased because of a rise in VLDL choles-
apo A-IV, and apo C-I are activators of lecithin:choles- terol, although HDL cholesterol is decreased.1,5 In addi-
terol acyltransferase13; and apo C-II is an activator of tion, chylomicron remnants and IDL accumulate.22
lipoprotein lipase.12–14 Normal lipoprotein metabolism In these humans, the normal apoprotein patterns of
TABLE II
Lipid Distribution in Normal Canine Plasma Lipoproteina
Lipoprotein Triglycerides Cholesterol Cholesteryl Esters c Phospholipids
Fractionb (mg/100 ml) (mg/100 ml) (mg/100 ml) (mg/100 ml)
VLDL 9.0 ± 1.7 2.3 ± 0.5 1.8 ± 0.5 2.5 ± 1.0
LDL 7.6 ± 1.8 5.7 ± 1.9 4.23 ± 0.2 6.4 ± 1.8
HDL1 0.3 ± 0.05 4.6 ± 1.4 3.4 ± 0.2 5.4 ± 1.3
HDL2 2.2 ± 0.3 70.0 ± 12.0 51.5 ± 1.3 124.6 ± 10.3
a From Mahley RW, Weisgraber KH: Canine lipoproteins and atherosclerosis I. Isolation and characterization of plasma lipoproteins
from control dogs. Circ Res 35:713–721, 1974. Reproduced with permission. Results are means ± SE from duplicate determinations
on plasma from four dogs.
b VLDL = very-low-density lipoprotein; LDL = low-density lipoprotein; and HDL = high-density lipoprotein.
c Expressed as cholesterol equivalents.
TABLE III
Normal Canine Plasma Lipid Levelsa
Triglycerides Total Cholesterol Cholesteryl Esters b Phospholipids
(mg/dl) (mg/dl) (mg/dl) (mg/dl)
Mean 36 127 97 302
Range 15–70 60–185 40–150 198–437
a Results are from duplicate determinations on plasma from 25 control dogs. From Mahley RW, Weisgraber KH: Canine lipoproteins
and atherosclerosis I. Isolation and characterization of plasma lipoproteins from control dogs. Circ Res 35:713–721, 1974. Reproduced
with permission.
b Expressed as cholesterol equivalents.
the lipoprotein classes are shifted. Apoprotein changes underlying mechanisms have been proposed. Consider-
include reduction in plasma levels of apo A-I, apo A-II, able evidence points to a reduction in lipoprotein lipase
and apo E and concurrent, marked elevation in apo C- activity in tissue and the liver,4,24 perhaps under the in-
III.5–7 Moderate elevations in apo C-I, apo C-II, and fluence of an inhibitor substance. 25 McCosh and
apo B may also be observed.7 Elevations in apo(a), coworkers reported hypertriglyceridemia and decreased
which is the apoprotein of Lp(a), also occur. Apo(a) is a postheparin lipolytic activity among renal-failure pa-
human apoprotein structurally similar to plasminogen. tients undergoing long-term dialysis.4 Notably, these re-
High plasma levels of its associated lipoprotein, Lp(a), searchers found that the reduction in posthepatic
have been found to be an important risk factor for lipolytic activity was directly proportional to the degree
coronary artery disease.23 of renal failure.4 Murase and coworkers reported that in
The described dyslipoproteinemia of chronic renal vitro activity of lipoprotein lipase was significantly low-
failure can be detected early in the course of disease5,7; er in uremic plasma than in normal plasma.25 Dialysis
the severity of the lipid abnormalities is directly propor- of the uremic sera before incubation with the enzyme
tional to the degree of renal azotemia.5 Attman and did not alter these results.25
Alaupovic7 showed that nondialyzed patients with early A study of dogs points to secondary hyperparathy-
renal failure exhibited characteristic changes in roidism as a potential cause of lipoprotein lipase defi-
apolipoprotein patterns. These apoprotein changes be- ciency.26 This study of dogs with experimentally in-
came more pronounced with increased severity of dis- duced renal failure showed that dogs that had also
ease and were associated with the development of hy- undergone parathyroidectomy have normal serum
pertriglyceridemia and hypercholesterolemia.7 triglycerides and postheparin lipolytic activity when
compared with the dogs that had not undergone
Pathogenesis parathyroidectomy. Excess parathyroid hormone is be-
The pathogenesis of the dyslipoproteinemia of lieved to suppress insulin release, thus resulting in car-
chronic renal failure is not fully understood, but several bohydrate intolerance. Insulin deficiency also causes
these complications. As outlined above, a growing body Valle D (eds): The Metabolic Basis of Inherited Disease. New
of evidence indicates that lipid abnormalities may also York, McGraw-Hill, 1989, pp 1129–1138.
12. Gotto AM, Pownall HJ, Havel RJ: Introduction of the plas-
be important in the progression of the renal disease. ma lipoproteins. Meth Enzymol 128:3–41, 1986.
Discovery of the role that lipids play in promoting re- 13. Scanu AM: Physiopathology of plasma lipoprotein
nal disease is especially important in light of the avail- metabolism. Kidney Int 39(suppl 31):S-3–S-7, 1991.
ability of drugs for the manipulation of lipoproteins 14. Nilsson-Ehle P, Garfinkel AS, Schotz MC: Lipolytic en-
and cholesterol. Continued research in this area of zymes and plasma lipoprotein metabolism. Annu Rev
Biochem 49:667–693, 1980.
nephrology may lead to better management and con- 15. Sherrill BC, Innerarity TL, Mahley RW: Rapid hepatic
trol of chronic renal disease and has the ultimate goal clearance of the canine lipoproteins containing only the E
of altering the progressive nature of renal disease. apoprotein by a high affinity receptor. J Biol Chem 255(5):
Dogs are certainly less susceptible to atherosclerosis 1804–1807, 1980.
than humans are, so cardiovascular complications are 16. Angelin B, Raviola CA, Innerarity TL, Mahley RW: Regula-
tion of hepatic lipoprotein receptors in the dog. Rapid regu-
less of a concern. However, the potential involvement lation of apolipoprotein B, E receptors, but not of
of dyslipoproteinemia in the progression of canine apolipoprotein E receptors, by intestinal lipoproteins and
chronic renal failure is an intriguing and as yet unex- bile acids. J Clin Invest 71:816–831, 1983.
plored area of canine nephrology. 17. Sehayek E, Eisenberg S: Mechanisms of inhibition by
apolipoprotein C of apolipoprotein E dependent cellular
metabolism of human triglyceride-rich lipoproteins through
the low density lipoprotein receptor pathway. J Biol Chem
About the Authors 266(27):18259–18267, 1991.
Drs. Down and Krawiec are affiliated with the Department 18. Mahley RW, Weisgraber KH: Canine lipoproteins and
of Veterinary Clinical Medicine of the College of Veteri- atherosclerosis. I. Isolation and characterization of plasma
lipoproteins from control dogs. Circ Res 35:713–721, 1974.
nary Medicine, University of Illinois, Urbana, Illinois. Dr. 19. Mahley RW, Weisgraber KH, Innerarity TL: Canine
Krawiec is a Diplomate of the American College of Veteri- lipoproteins and atherosclerosis. II. Characterization of the
nary Internal Medicine. plasma lipoproteins associated with atherogenic and
nonatherogenic hyperlipidemia. Circ Res 35:722–733, 1974.
20. Mahley RW, Weisgraber KH: Canine plasma lipoproteins:
Characterization of lipoproteins from control and choles-
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